Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure

Garbincius, Joanne F; Luongo, Timothy S.; Jadiya, Pooja; Hildebrand, Alycia; Kolmetzky, Devin W.; Mangold, Adam S; Roy, Rajika; Ibetti, Jessica; Nwokedi, Mary; Koch, Walter J.; Elrod, John W.

doi:10.1016/j.yjmcc.2022.03.001

Cited by 21 publications

(24 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Osmotic minipump implantation surgeries were performed as detailed previously 35 . Mice were anesthetized with 3% isoflurane and an osmotic minipump (Alzet model 2004, #0000298) set to deliver (±)-isoproterenol hydrochloride (Sigma-Aldrich #I5627) dissolved in sterile saline at a dose of 70mg/kg/day for 2 weeks was inserted subcutaneously via a small midline incision in the back.…”

Section: Isoproterenol Infusionmentioning

confidence: 99%

“…Heart sections were labelled with TRITC-conjugated wheat germ agglutinin (Sigma-Aldrich #L5266) at 100µg/mL to outline each cell, and coverslips were mounted using ProLong Gold Antifade Mountant with DAPI (Invitrogen #P36935). Slides were imaged and cardiomyocyte crosssectional area measured as described previously 35 . Lung wet mass was measured at the time of collection, and lung dry mass was measured after drying the tissue at 37 o C for 48 hours for assessment of lung edema.…”

Section: Tissue Gravimetrics and Histologymentioning

confidence: 99%

See 1 more Smart Citation

MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure

Garbincius

Luongo

Lambert

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Mitochondrial calcium (mCa2+) uptake through the mitochondrial calcium uniporter channel (mtCU) stimulates metabolism to meet acute increases in cardiac energy demand. However, excessive mCa2+ uptake during stress, as in ischemia-reperfusion, initiates permeability transition and cell death. Despite these often-reported acute physiological and pathological effects, a major unresolved controversy is whether mtCU-dependent mCa2+ uptake and long-term elevation of cardiomyocyte mCa2+ contributes to the heart's adaptation during sustained increases in workload. Objective: We tested the hypothesis that mtCU-dependent mCa2+ uptake contributes to cardiac adaptation and ventricular remodeling during sustained catecholaminergic stress. Methods: Mice with tamoxifen-inducible, cardiomyocyte-specific gain (αMHC-MCM x flox-stop-MCU; MCU-Tg) or loss (αMHC-MCM x Mcufl/fl; Mcu-cKO) of mtCU function received 2-wk catecholamine infusion. Results: Cardiac contractility increased after 2d of isoproterenol in control, but not Mcu-cKO mice. Contractility declined and cardiac hypertrophy increased after 1-2-wk of isoproterenol in MCU-Tg mice. MCU-Tg cardiomyocytes displayed increased sensitivity to Ca2+- and isoproterenol-induced necrosis. However, loss of the mitochondrial permeability transition pore (mPTP) regulator cyclophilin D failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased isoproterenol-induced cardiomyocyte death in MCU-Tg mice. Conclusions: mtCU mCa2+ uptake is required for early contractile responses to adrenergic signaling, even those occurring over several days. Under sustained adrenergic load excessive MCU-dependent mCa2+ uptake drives cardiomyocyte dropout, perhaps independent of classical mitochondrial permeability transition pore opening, and compromises contractile function. These findings suggest divergent consequences for acute versus sustained mCa2+ loading, and support distinct functional roles for the mPTP in settings of acute mCa2+ overload versus persistent mCa2+ stress.

show abstract

Section: Isoproterenol Infusionmentioning

confidence: 99%

Section: Tissue Gravimetrics and Histologymentioning

confidence: 99%

MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure

Garbincius

Luongo

Lambert

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mitochondrial homeostasis plays a crucial role in cells with high energy consumption, and in the pathological development of ischemic heart disease [ 30 ]. In particular, variation in the level of Ca 2+ in mitochondria could lead to altered contraction coupling [ 31 ] and increased ROS levels during ischemic myocardial reperfusion, thereby inducing mitochondrial membrane damage, abnormal ATP synthesis, increased levels of Ca 2+ , and mPTP opening [ 32 ].…”

Section: Mechanism Of Mitochondrial Dysfunction and Molecular Implica...mentioning

confidence: 99%

Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Ciccarelli

Conte

Cimmino

et al. 2023

IJMS

View full text Add to dashboard Cite

Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.

show abstract

“…The calcium hydrogen exchanger functions independently of sodium and is present at much lower activities in tissues with high energy demand [ 28 ]. For instance, the CHE is dominant in the liver and other relatively quiescent tissues, while NCLX is predominant in the heart, brain, and other high activity tissues [ 29 , 30 , 31 , 32 , 33 , 34 ].…”

Section: Calcium Homeostasis Entry and Exit Pathwaysmentioning

confidence: 99%

Calcium Overload and Mitochondrial Metabolism

Walkon,

Strubbe-Rivera,

Bazil

2022

Biomolecules

View full text Add to dashboard Cite

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events.

show abstract

Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure

Cited by 21 publications

References 106 publications

MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure

MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure

Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Calcium Overload and Mitochondrial Metabolism

Contact Info

Product

Resources

About